Compensatory role of thyroid hormone receptor (TR)α1 in resistance to thyroid hormone: Study in mice with a targeted mutation in the TRβ gene and deficient in TRα1

Abstract

Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor β (TRβ) gene. Almost all RTH patients are heterozygous with an autosomal dominant pattern of inheritance. That most are clinically euthyroid suggests a compensatory role of the TRα1 isoform in maintaining the normal functions of thyroid hormone (T3) in these patients. To understand the role of TRα1 in the manifestation of RTH, we compared the phenotypes of mice with a targeted dominantly negative mutant TRβ (TRβPV) with or without TRα1. TRβPV mice faithfully recapitulate RTH in humans in that these mice demonstrate abnormalities in the pituitary-thyroid axis and impairment in growth. Here we show that the dysregulation of the pituitary-thyroid axis was worsened by the lack of TRα1 in TRβPV mice, and severe impairment of postnatal growth was manifested in TRβPV mice deficient in TRα1. Furthermore, abnormal expression patterns of T3-target genes in TRβPV mice were altered by the lack of TRα1. These results demonstrate that the lack of TRα1 exacerbates the manifestation of RTH in TRβPV mice. Therefore, TRα1 could play a compensatory role in mediating the functions of T3 in heterozygous patients with RTH. This compensatory role may be especially crucial for postnatal growth.